Age-related macular degeneration (AMD), the leading cause of incurable blindness among older adults in the US, is caused by interactions between underlying genetic susceptibility and lifestyle risk factors. However, our knowledge of the network of contributors to the pathogenesis of AMD remains incomplete, and treatment is inadequate. The proposed studies build upon a strong and growing foundation of research and invaluable existing resources to comprehensively study the genetic epidemiology of AMD. Through its use of archived DNA specimens from several large prospective cohort studies, this proposal represents a cost-effective, efficient, and informative approach to investigate the following specific aims: 1) determine the incidence rate ratio and attributable fraction for AMD in relation to common variants within a group of strong candidate genes including complement factor H, HTRA1/LOC387715, and others (candidates identified based on position, function, expression, etc.) using both single locus and haplotype analyses for AMD overall as well as for both dry and neovascular subtypes, 2) effectively utilize data derived from RNA microarray analysis of sibpairs extremely discordant for AMD to inform selection of candidate genes, 3) estimate the magnitude and significance of any gene-gene, or gene-environment interactions among these candidates and risk factors such as cigarette smoking, obesity, diet, and serum inflammatory markers. These aims will be accomplished through genotyping of >1300 confirmed incident AMD cases and >3000 controls in our high-tech core genotyping facility, along with direct sequencing when indicated for SNP discovery as well as to search for functional variants or disease-causing mutations if association analyses are significant. Unique strengths of this approach include the prospective design, large sample size, high-quality, high-throughput genotyping, integration with a study of extremely discordant sib-pairs, and state-of-the-art statistical analyses to provide precise estimates for effects of genes, gene-gene and gene-environment interactions. The proposed studies minimize bias through prospective assessment of exposures and AMD status, direct estimation of incidence rate ratios, novel candidate gene selection, and high statistical power. The long-term objective and clinical relevance of this research is to shed light on underlying biological mechanisms relevant to AMD, to suggest avenues for novel preventive or therapeutic approaches, and identify clinically useful risk assessments.